1-oxygenated androstanes



United States Patent 3,405,125 l-OXYGENATED ANDROSTANES Klaus Irmscher, Darmstadt, and Karl-Heinz Bork, Darmstadt-Arheilgen, Germany, asslgnors to E. Merck A.G., Darmstadt, Germany No Drawing. Continuation-impart of application Ser. No. 328,121, Dec. 4, 1963. This application Apr. 18, 1966, Ser. No. 543,087

6 Claims. (Cl. 260-2395) ABSTRACT OF THE DISCLOSURE Reductively splitting a 1a,2a-oxido-3-keto-steroid with an alkaline metal or an alkaline earth metal in either liquid ammonia, primary amine, or secondary amine, the ratio of the metal to the starting material being about 1:1 to 1:15, respectively; the resultant l-oxygenated, 3-keto androstanes having a free or esterified 17-hydroxyl group being useful for their anabolic and/or androgenic activity.

This invention relates to the preparation of lot-hydroxy- 3-keto steroids and the esters and ethers thereof.

An object of this invention, therefore, is to provide novel and unobvious 1u-hydroxy-3-keto steroids, particularly steroids of the androstane series, and their esters and ethers.

Another object is to provide a novel and unobvious process for the production of the novel steroids of this invention.

Still another object is to provide novel and unobvious pharmaceutical compositions based on the steroids of this invention.

Yet another object is to provide processes for effecting therapeutic activity, using the steroids of this invention.

Upon further study of the specification and claims, other objects and advantages of the present invention will become apparent.

To attain the objects of this invention, there are provided 1a-hydroxy-3-keto steroids as well as their esters and ethers of the formula:

QRi

I wherein R 'represents any of hydrogen; alkyl of not more than 6 carbon atoms; cycloalkyl of not more than 6 carbon atoms; and acyl, preferably alkanoyl, of not more than 18 carbon atoms;

R represents H or OH;

R represents H or F;

R represents any of alkyl, alkenyl, and alkynyl, none of which contains more than 3 carbon atoms; and hydrogen; and

R represents a free or esterified hydroxy group wherein the esterifying moiety contains up to 18 carbon atoms.

Two preferred groups of compounds are:

(1) androstane-1u,17,9-diol-3-one, and the monoesters, diesters, and the l-lower alkyl ethers thereof; and

(2) 17a-methyl-androstane-1a,17fl-diol-3-one, and the monoesters, diesters, and l-lower alkyl ethers thereof.

Patented Oct. 8, 1968 "ice The preferred species are:

androstane-1a,17p-diol-3-0ne-17-acetate androstane-1u,17,8-diol-3-one-17-propionate androstane-1a,17/3-diol-3-one-17-cyclohexyl-propionate androstane-1a,17 3-diol-3-one-17-nicotinate l-methyl-ether of androstane-1a,17 3-diol-3-one- 17-acetate l-methyl-ether of androstane-1a,17B-diol-3-one- 17-propionate l-methyl-ether of androstane-1oz,17fi-diol-3-one- 1 7-cyclohexyl-propionate l-methyl-ether of androstane-1a,17,8-diol-3-one- 17-nicotinate androstane-1a,17fl-diol-3-one-1,17-diacetate androstane-1a,17fi-diol-3-one-1-acetate-l7-propionate androstane-1a,17,8-diol-3-one-1-acetate-17-cyclohexylpropionate androstane-1a,17B-diol-3-one-l-acetate-17-nitcotinate l7a-methyl-androstane-1a,17(3-diol-3-one l-methyl-ether of 17a-methyl-androstane-1a,17[3-diol 3-one 17a-methyl-androstane-1a, 17/8-diol-3-one-1-acetate.

These compounds are produced by reacting a 111,20;- oxido-3-keto-steroid with an alkali metal or alkaline earth metal in either liquid ammonia or a primary or secondary amine.

According to this invention, the reaction can also be performed in the presence of an alcohol, preferably a lower aliphatic alcohol and/ or another solvent inert under the reaction conditions. It is then also possible to esterify or etherify the resultant hydroxy-steroid in the conventional manner.

It is to be appreciated that during the conversion of a 1a,2a-oxido-3-keto-steroid, the 3-keto group remains intact under the reaction conditions of this invention. This is completely unexpected because it was made known by the reports in the J. Am. Chem. Soc., vol. 78, pp. 6302 et seq. (1956) and vol. 80, p. 6117 (1958), that under the reaction conditions of this invention, keto groups in the 3-position would be reduced to the corresponding secondary alcohol groups. Therefore, it would have been assumed by those skilled in the art that the process of this invention would produce not 1a-hydroXy-S-keto-steroids, but rather the corresponding lu,3-dihydroxy-steroids.

Even though it was known that epoxides could be reduced to alcohols by alkali metals in liquid ammonia or amines, and that this method is also applicable to the steroid series (see J. Chem. Soc. [London], vol. 1957, p. 4604), no reaction of this kind has been described which can be performed in the presence of a keto group, because as is known, keto groups under the reaction conditions are reduced to the corresponding alcohols. It was also unexpected that the reaction would produce only the Ia-hydroxy steroid and not a mixture of 1- and 2- hydroxy steroids, and especially since the theoretically obtainable 2-hydroxy steroid and also the actually obtained l-hydroxy steroid are both secondary alcohols.

The process of this invention can be performed in liquid ammonia or in a primary or secondary amine. Although generally all primary and secondary amines are suitable for this reaction, it is advantageous in this invention to use those amines which do not contain more than 10 carbon atoms and also not more than 2 amino groups. Use is preferably made of nand isopropylamine, n-butylamine, isobutylamine, secondary butylamine, diethylamine, di-n-propylamine, diisopropylamine, aniline, monomethyl-aniline, or cyclohexylamine. The amine is so chosen that it is a liquid under the reaction conditions employed. The reaction temperatures that are used preferably lie between C. and +100 C.

"As'alkali or alkaline earth metals, use is preferably made of lithium, sodium, potassium, or calcium.

The molar ratio of the initial steroid to the alkali metal or alkaline earth metal lies generally between 1:1 and 1:15, whereas the ratio of the initial steroid to the ammonia is in no way critical.

It is sometimes beneficial to perform the reduction in the presence of an alcohol which functions to accelerate the reaction.

Preferably, a lower aliphatic alcohol, such as methanol or ethanol,'is used for this purpose, the ratio of the alcohol to initial steroid being about 0.2:1 to 10:1, expressed as molar ratio. Here also the reaction is performed at temperatures within the above range. The solvents that are used, namely liquid ammonia or a primary or secondary amine, are also the same as those mentioned above. Instead of or in addition to the lower aliphatic alcohol, other inert solvents can also be used, such as ether, tetrahydrofuran, dioxane, or hydrocarbons, such as benzene, toluene, or petroleum ether. The inert solvent increases the solubility of the starting material in the reaction mixture and is generally added in a quantity sufficient to dissolve the initial steroid.

The solution containing the reaction products is worked up in the usual manner, as by reaction with water, a mineral acid, or ammonium chloride, with subsequent isolation by extraction, chromatography, and/ or crystallization.

According to this invention it is also possible to esterify or etherify the hydroxyl groups of the hydroxysteroids obtained by the above-described reduction. For etherifying, use can be made of the usual reactive derivatives of those alcohols which form physiologically compatible ethers. Among such alcohols can be mentioned methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, teritary butanol, cyclopentanol, and cyclohexanol, this list, however, being not exhaustive.

Alcohol derivatives which can be advantageously used for etherifying are the iodide, bromide, chloride, methylsulfonate, p-toluenesulfonate, or diazo derivatives (e.g. diazomethane). As condensation agents for promoting the etherification, use can be made of acids, especially acids such as BF or NaBF or bases such as 'alcoholates or sodium hydride. Especially good results are obtained with silver bases, such as silver oxide, silver hydroxide, or silver carbonate.

As esterification agents, use can be made of all acids or suitable acid derivatives which form physiologically compatible esters. For example, the following acids or their esterifiable derivatives can be employed: carboxylic acids, such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, trimethylacetic acid, tertiary butylacetic acid, caproic acid, enanthic acid, caprylic acid, palmitic acid, undecanoic acid, benzoic acid,

hexahydrobenzoic acid, cyclopenthyl-, cyclohexyl-, or aryl- I acetic acids and -propionic acids, such as phenylacetic or cy clohexylpropionic acid, ether-acids, e.g. p-butoxybenzoic acid or heterocyclic acids, such as furancarboxylic acid-2 or nicotinic acid. Besides the free acids, some of their derivatives, such as their halides, anhydrides, thio-derivatives and ketenes are also suitable for esterification, as are the lower alkyl esters for re-esterification methods. If, in addition to the lot-hydroxy groups, other secondary hydroxy groups are also present in the molecule, they also will be reacted during the etherification or esterification.

The process can be used generally for all 10,2ot-OXidO- 3-keto-steroids of the androstane series. The oxido-steroids that are used as starting materials can therefore be substituted in various ways, e.g. on the C-atoms 2, 4, 9, ll, 16, or 17. Preferred substituents are e.g. alkyl groups, such as methyl or ethyl groups, alkylidene groups, such as methylene or ethylidene groups, halogen substituents, e.g. fluorine, hydroxyl groups which may be in the form of esterified, etherified, or acetal groups, as well as carbonyl groups. The latter, if they are not 3-keto groups, are reducible under the conditions of this process. Such areduction may be desired. If it is to be prevented, then the carbonyl groups in question can be protected by functional conversion, e.g. into acetals, enol-ethers, or enamines.

From the group of possible starting materials, the most important ones are those which are represented by the following formula:'

wherein I R and R H or a lower alkyl, preferably a methyl p;

R =H or acyl containing up to 18 carbon atoms;

R =H or a lower alkyl, alkenyl, or alkynyl group with up to 3 carbon atoms;

R7=H or a lower alkyl or alkylidene group, preferably methyl or methylene. 1

Under the specified reaction conditions, the 1a,2otoxido-Zfi-methyl-steroids yield 10: hydroxy 2a. methyl compounds because after the oxido ring has been opened, the methyl groups migrate into the more stable a-position.

Preferred starting materials for the process of this invention are, e.g., 1a,2a-oxido-androstane-3-one-175-ol, as well as its l7-esters, 1a,2a-oxido-17a-methyl-androstane-3-one-17/8-ol; 1a,2a oxido-17ot-ethyl-androstane-3- one-17,3-ol; 1(X,2tl oxido-17a-allyl-androstane-B-one-17pol; 1a,2a-oxido-17a-ethynyl-androstane 3 one 17p ol; 1a,2a oxido 9a-fluoro-11 it-hydroxy-17a-methyl-androstane-3-one-17B-ol. 1

The IOQZIXOXidO-Stfil'OldS which are used as starting materials can be obtained from the original unsaturated steroids, namely from the 3-keto-1-androstenes by the usual treatment with a peracid, e.g. perbenzoic acid or monoperphthalic acid, or with alkaline hydrogen peroxide. For additional details, reference is respectfully directed to the method described by P. Striebel et al. in Helv. Chim. Acta, vol. 37, page 1094 (1954).

Some of the starting materials are known, e.g. from J. Org. Chemistry, vol. 27, page 248 (1962) and from German Patent No. 1,096,356.

In general, all starting compounds may be prepared in a known manner from the corresponding 4-androstene- 3-keto-steroids which are coverted by the action of Li/NH into the corresponding saturated 5a-androstanes. These are bromated with bromine and subsequently treated with LiBr/Li CO in dimethyl formamide whereby HBr is split off and the corresponding l-androstenes are obtained.

4-androstene-3-keto-steroids to be used in the preparation of the starting materials are described, for example, in: v

J. Am. Soc., vol. 81, p. 427 (1959); J. Chem. Soc. 1962, p. 1091; Chemische Berichte, 1961, p. 2897; J. Med. Chem, 1963, p. 178; German Patents 1,097,985, 1,117,114, 1,124,489; British specifications 801,024, 801,422, 809,485, 855,300.

The 16-methyl compounds used as starting materials are, for example, available from 1611- and 16fl-methylandrostenolone as described by P. de Ruggieri et al. in Gaz. chim. ital. (1961), p. 672. Reaction with Li-alkyl (Grignard reaction) yields the corresponding 17a-alkyl- 17B-OH-compound which is then catalytically hydrogenated in the 5-position and the 3fl-OH group is oxidized, preferably with chromic acid, these reactionsresulting in the formation of 16-methyl-3-keto-androstanes. Upon dehydrogenation in the l-position and treatment with a peracid as described above, the starting materials according to Formula II are obtained.

The 17B-hydroxy group of any starting material may be converted into an ester group containing up to 18 carbon atoms according to the methods described hereina-bove.

It is to be noted that the preparation of the starting materials will cause no difiiculties to one skilled in the art since all processes and reaction steps are well known in the art.

The hydroxy-steroids which are obtained as end products of the process of this invention, and which, if necessary, can be etherified 'or esterified are characterized by their outstanding pharmacological effectiveness. They exhibit anabolic, androgenic, and antiestrogenic activity.

The new compounds can be used in admixture with the usual pharmaceutical carriers and excipients. Suitable carrier substances are those organic or inorganic materials which are suitable for parenteral, enteral, or topical application and which do not react with these new compounds, as for example water, vegetable oils, polyethylene glycol, gelatin, lactose, starch, magnesium stearate, talc, Vaseline, cholesterol, etc. For parenteral application, solutions are especially suitable, and preferably oily or watery solutions as well as suspensions or emulsions. For ente-ral application tablets or dragees can also be used,,while for topical application use can be made of salves or creams which can, if necessary, be sterilized or mixed with ancillary materials, such as preservatives, stabilizers, Wetting agents, salts to influence the osmotic pressure, or buffer substances.

In pharmaceutical preparations, the active substances are generally present in dosages of 0.5 to 300 mg.

The pharmaceutical preparationscontaining the new compounds of this invention are to be used as drugs. in all indications where anabolic, androgenic, and antiestrogenic effects are desired. They may be combined as well with other active compounds with which they are compatible.

The novel compounds of this invention canbe administered to mammals. For example, by administering androstane-1a,17B-diol-3-one to a rat, a strong anabolic effect is obtained, and with this particular drug a relatively low androgenic effect is also obtained-which gives the drug a desirable anabolic/androgenic index.

In addition, some of the compounds of this invention, especially androstane-1a,17fl-diol-3-one, intermediates in the production of useful androstanes. For example, androstane-1a,17 3-diol-3-one may be converted by standard procedures into the 1u,17/3-diacetate or -dipropionate.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the specification and claims in any way whatsoever.

EXAMPLE 1 (a) 2 g. 1a,2a-oxido-androstane-17fl-ol-3-one are dissolved in 25 cc. absolute tetrahydrofuranand that solution is added, drop-by-drop, to a solution of 0.1 g. lithium in 80 cc. anhydrous liquid ammonia with continual stirring. After minutes, 30 cc. saturated aqueous ammonium chloride solution are slowly added. The resultant mixture is allowed to stand overnight to permit the ammonia to evaporate. It is then dissolved in chloroform, washed in water, in 5% bicarbonate solution, and again in water, and finally dried over sodium sulfate and freed from solvent. The residue is chromatographed on 80 g. silica gel. The androstane-1a,17p-diol-3-one is eluted with chloroare valuable 6 form-acetone 4:1, and is purified by recrystallization from acetone. M.P. 253 C.; [a];, +20 (chloroform).

(b) 2.1 g. androstane-1a,17B-diol-3-one are allowed to stand overnight at room temperature with 9 cc. absolute pyridine and 9 cc. acetic anhydride. The deposit is stirred into 750 cc. water and the precipitated androstane-1a, l7/3-diol-3-one-1,17-diacetate filtered with suction, dried, and recrystallized from acetone. M.P. 187 C.; [(11 +60 (chloroform). a 1

EXAMPLE ,2

(a) 4 g. 1a,2a-oxido-17u-methyl-androstane-17,8-01-3- one are reduced with lithium and ammonia as in Example 1(a). The crude product is chromatographed on g. silica gel. The liberated 17a-methyl-and-rostane-1a, 17,8-diol-3-one is removed from the-column by chloroform-acetone 4:1 and is purified by recrystallization from acetone. M.P. 216 C.; [111 +11 (chloroform).

The reaction can be performed with calcium instead of lithium.

(b) 1 g. l7a-me-thyl-androstane-la,l7fi-diol-3-one is boiled under reflux 2 hours with 5 cc. chloroform and5 cc. acetic anhydride. The solvent is filtered 01f and the crude product chromatographed with silica gel. The methyl-androstane-1a,17 8-diol-3-one-l-acetate is recrystallized from ether. M.P. 1l01l2 C.

(c) The product of Example 2(a) is converted into the l-methyl ether of l7a-methyl-androstane-10:,17B-di0l- 3-or;e by analogy to the method described in Example 3(b EXAMPLE 3 (a) By analogy to Example 1(a), 3 g. la,2a-oxidoandrostane-l7B-Ol-3-One-17-pr0pi0nate are reduced by lithium in liquid ammonia to androstane-1a,17fi-diol-3- one-17-propionate and purified by chromatography, the reaction mixture being fractionated after only 5 minutes with ammonium chloride.

(b) 3 g. androstane-1a,l7/3-diol-3-one-l7-propionate are dissolved in 7 cc. dimethyl formamide and reacted with 5.2 g. silver carbonate and 5.4 g. methyl iodide. The solution is stirred 48 hours at room temperature, the silver salts filtered off, and the material worked up with methylene chloride and water. The crude product is purified by chromatography with 120 g. silica gel. The separated 1- methyl-ether of the androstane-1a,17,8-diol-3-one-l7-propiorlate is removed from the column with benzene-chloroform 1:4 and recrystallized from ether/petroleum ether. M.P. 137-138 C.; [ofl +48 (chloroform).

Similarly androstane 1a,175 diol 3 one l7 acetate (M.P. 230-233" C.) is obtained from 1a,2oz-0Xid0 androstane 17fl-ol-3-one-l7-acetate and can be converted into the corresponding l-methyl-ether by analogy to EX- ample 3 (b).

(c) By analogy to Example 2(b) the androstane-la, 17B-diol-3-one-17-propionate obtained in Example 3(a) is converted into the androstane-1a,17p-diol-3-one-1-acetate-17-propionate.

EXAMPLE 4 (a) By analogy to Example 3(a), 1.2 g. 1a,2a-oxidoandrostane 17B ol 3 one 17 ([B cyclohexyl]- propionate) (M.P. 154 C.) are reduced by lithium in liquid ammonia to androstane-1a,17fl-diol-3-one-17-([,B- cyclohexyl]-propionate) which is isolated by chromatography with silica gel and is recrystallized from acetone. M.P. 220-222 C.

(b) By analogy to Example 3(b), the androstane-1a, 17/3 diol 3 one 17 ([19 cyclohexyl]-propionate) obtained in Example 4(a) is converted into the corresponding l-methyl-ether. I

(o) By analogy to Example 2(b), the androstane-1oz, diol 3 one 17 ([1 cyclohexyl] propionate) obtained in Example 4(a) is converted into the corresponding l-acetate.

7 EXAMPLE (a) 4 g. 1a,2a-oxido-17a-ethynyl-androstane-175-01-3- one are reduced with lithium or sodium in ammonia as in Example 1(a). The crude product is chromatographed with 180 g. silica gel. The l7a-ethynyl-androstane-1a,17 8 diol-3-one is recrystallized from acetone.

(b) The compound obtained in Example 6(a) is treated with cyclohexyl bromide in the presence of sodium methylate in a known manner to convert it into the 170: ethynyl androstane :,17 3 -diol 3 one 1- cyclohexyl-ether.

EXAMPLE 7 1.5 g. 1u,2a-oxido-17a-ethyl-androstane-17fl-ol-3-one by analogy to Example 1(a) are reduced to 17a-ethyl-androstane-1u,17;8-diol-3-one.

Instead of ammonia, a mixture of aniline and tetrahydrofuran can be used in this reaction.

EXAMPLE 8 By analogy to Example 1(a), 1.8 g. of 10,2a-OXidO-9otfluoro-androstane 116,175 diol-3-one-17-enanthate are converted into 9a fiuoro-androstane-la,11,8,17B-triol-3- one-17-enanthate. The product is worked up in the usual manner and recrystallized from acetone/petroleum ether.

EXAMPLE 9 (a) By analogy to Example 1(a), 5 g. 1a,2a-OXidO- androstane-l7fl-ol-3-one-17-nicotinate are converted into androstane-1a,17B-diol-3-one-17-nicotinate.

(b) By analogy to Example 3(b), the compound obtained in Example 9(a) is converted into the l-methyl ether of androstane-la,17 8-diol-3-one-l7-nicotinate.

(c) By analogy to Example 2(b), the compound obtained in Example 9(a) is converted into the androstane- 1a,l7 8-diol-3-one-l-acetate-17-nicotinate.

EXAMPLE 10 By analogy to Example 1(a), 2.8 g. 1u,2ot-0XidO-2 3,17ocdimethyl-androstane-17fi-ol-3-one are reduced to Zu-methyI-androstane-la,17fi-diol-3-one.

EXAMPLE 11 (a) By analogy to Example 1(a), 1.7 g. 1a,2u-oxido- 16 methylene-androstane-17fl-ol-3-one-acetate are converted into the 16 methylene-androstane-la,17B-diol-3- one-17-acetate.

(b) By analogy to Example 6(b), the compound obtained in Example 11(a) is reacted with butyl bromide to convert it into the l-butyl ether of the l6-methylene-androstane-la,17/3-diol-3-one-17-acetate.

EXAMPLE 12 (a) By analogy to Example 1(a), 3.1 g. 101,2oz-0Xid0- 9o: fiuoro-17a-methyl-androstane-11fi,17;8-diol-3-one are reduced to 90 fluoro-17a-methyl-androstane-1a,11B,17 8- tri0l-3-one.

(b) 1.8 g. of the product obtained from Example 12(a) are reacted in the usual manner with undecylenic acid chloride in pyridine. The reaction mixture is allowed to stand overnight, is then poured into water, and the 90:- fiuoro-17 8-methyl-androstane 101,115.17fl-triol-3-one-1- undecylenate is then extracted with chloroform.

If instead of undecylenic acid chloride, the chloride of furane-carboxylic acid is used, the corresponding l-furanate will be obtained.

EXAMPLE 13 (a) From 2.2 g. 1a,2 x-oxido-l6fi-methyl-androstane- 17,8-ol-3-one, there will be obtained by the process of Example 1( a), the 16fl-methyl-androstane-1a,17fl-diol-3-one.

(b) The product obtained in Example l3( a) is reacted with 3,3-dimethyl-butyryl-chloride in pyridine to produce 16fl-methyl-androstane-lu,l7fi-diol-3-one 1,17 ditert.- butyl acetate.

EXAMPLE 14 (a) 1.8 g. of lulu-oxida-16a-methyl-androstane-17,8- ol-3-one-parabutoxy-benzoate are reduced by the method of Example 1(a) to 16a-methyl-androstane-1u,17B-diol-3- one-17-parabutoxy-benzoate.

(b) By analogy to the method of Example 6(b), the compound obtained in Example 14(a) is converted into the corresponding l-tert.-butyl ether.

Examples for pharmaceutical preparations:

(A) Injection solution 2 g. of androstane-la,17fi-diol-3-one-17-cyclohexyl-propionate are dissolved in 1000 cc. of peanut oil. Ampoules are filled with 1 ml. of this solution each and are sterilized in the usual manner.

(B) Injection solution Each ampoule contains:

10 mg. of androstane-1a,17fl-diol -3-one-17-cyclo-hexylpropionate dissolved in 1 cc. of peanut oil. The ampoules are preferably filled under nitrogen.

(C) Tablets One tablet contains:

Mg. 17a-methyl-andr0stane-1a,17fi-diol-3-one 5 Corn starch 15 Lactose Talc 10 (D) Injection solution 5 g. of androstane-la,l7fl-diol-3-one-1,l7-diacetate are dissolved in ml. of peanut oil. The solution is filled into ampoules according to standard procedures in a manner that each ampoule contains 50 mg. of the active ingredient.

(E) Tablets Each tablet contains:

Mg. 17a-methyl-androstane-1a,l7fi-diol-3-one-1-acetate 5 Lactose 80 Potato starch 10 Magnesium stearate 2 (F) Injection solution Each ampoule contains:

50 mg. of androstane-la,17 8-diol-3-one-17-propionate in 1 cc. of peanut oil. The ampoules are sterilized according to standard procedures.

(G) Tablets One tablet contains:

Mg. Androstane-1a,17B-diol-3-one 2 Lactose 75 Corn starch 16 Talc 6 Magnesium stearate 1 The determination of the anabolic and androgenic effectiveness was made through the musculus levator ani and the spermatic gland weight test according to the method disclosed by Hershberger, Shipley, and Meyer in Proceedings of the Society for Experimental Biology and Medi- 9. cine, vol. 83, pp. 175-180 (1953). The rats were treated with the new compounds by oral and by subcutaneous administration.

Androstane-1a,17fl-diol-3-one, 17oz methylandrostane- 1a,17;8-diol-3-one and androstane :,17fl-di01-3-0116-17- cyclohexylpropionate show a good index of anaboliczandrogenic activity whereas the index of androgeniczanabolic activity is remarkable for androstane-1a,17 3- diol-3-one 17 propionate and the corresponding 1,17- diacetate. The introduction of the Ia'OH group into androstane l7fl-ol-3-one 17-acetate yielding androstane- 141,175 diol 3 one 17 acetate approximately doubles the anabolic activity whereas the introduction of said substituent into androstane-17fl-ol-3-one yielding androstane 1a,17;3-diol-3-one surprisingly increases this activity about ten-fold.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Consequently, such changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of the following claims.

What is claimed is:

1. A compound of the formula QCHa wherein R is a member of the group consisting of acetyl, propionyl, cyclohexylpropionyl, and nicotinyl.

2. l-methyl-ether of 17a methyl-androstane-la,17fldiol-3-one.

3. A process for the reductive splitting of an oxido ring in 3-keto steroids without reducing the S-keto group, which process comprises reacting at C. to +100 C. a 1at,Za-OXidO-3-k6tO-St6l'0id of the androstane series with a metal selected from the group consisting of an alkali metal and an alkaline earth metal, in a liquid medium selected from the group consisting of liquid ammonia, a primary amine, and a secondary amine with up to 10 carbon atoms and less than 3 amino groups, the molar ratio of metal to the 1a,2a-oxido3-keto-steroid being about from 1:1 to 1:15 to form the corresponding lat-hydroxy3-ketosteroids.

4. The process of claim 3 wherein the reaction is carried out in the presence of an aliphatic alcohol containing from 1 to 5 carbon atoms.

5. The process of claim 3 wherein the reaction is carried out in the presence of an inert solvent selected from the group consisting of ether, tetrahydrofuran, dioxane, benzene, toluene, and petroleum ether.

6. The process of claim 3 wherein the reaction is carried out in the presence of an aliphatic alcohol containing from 1 to 5 carbon atoms and an inert solvent selected from the group consisting of ether, tetrahydrofuran, dioxane, benzene, toluene, and petroleum ether.

References Cited UNITED STATES PATENTS 3,118,916 1/1964 Goedicke 260397.4 3,131,125 4/1964 Wettstein et al 16765 H. A. FRENCH, Primary Examiner. 

